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Erythropoietin promotes functional recovery via anti-apoptotic mechanisms in mice unilateral ureteral obstruction Park, Elliya

Abstract

The ureter transfers urine from the kidney through sequential contractions, called peristalsis. When obstructed, accumulated urine builds up high pressure which leads to dysfunction in the urological tracts. Our laboratory showed that, in mice, ureteral peristalsis is not recovered for 10 days after removing a 24-hour obstruction. Delayed ureteral recovery affects the kidney negatively as the ureter cannot transport urine properly. Studies have shown that erythropoietin (EPO), a hematopoietic hormone, protects different organs against various injuries mainly by suppressing apoptosis, via EPO receptor (EPOR) and β-common receptor (βCR) heterodimers. Our laboratory showed that prophylactic EPO treatment of obstructed mice accelerated recovery of the ureter and the kidney following the reversal of ureteral obstruction. We hypothesized that EPO treatment promotes functional recovery of the ureter and the kidney via anti-apoptotic mechanisms. The objective of this study was to investigate EPO-induced mechanisms in accelerating recovery from ureteral obstruction in 2 mice strains. Unilateral ureteral obstruction was created for 24, 48, 72 hours using non-traumatic micro-clip (n=10). EPO was administered daily for 4 days either prophylactically or concomitantly with ureteral obstruction. TUNEL assay and immunohistochemistry with phospho-NF-κB p65 and phospho-STAT5 antibodies on ureteral tissues and qRT-PCR with primers specific to EPO, EPOR, βCR, STAT5A, BCL-2, BCL-XL, BAX and NF-κB on ureteral and renal tissues were performed. Our study showed that ureteral obstruction decreased ureteral peristalsis and increased apoptosis in 72-hour obstructed ureters. Ureteral obstruction decreased anti-apoptotic EPOR-βCR signaling and increased phospho-NF-κB p65. EPO treatment on ureteral obstruction improved ureteral function and suppressed apoptosis in obstructed ureters, by suppressing NF-κB and decreasing apoptotic BAX. EPO treatment did not induce erythropoiesis in our study, which supports that EPO’s protective effect is a separate mechanism from increased blood circulation by hematopoiesis. Also, EPO treatment without obstruction did not change EPOR-βCR signaling. In conclusion, ureteral obstruction increased apoptosis in ureteral tissues and decreased anti-apoptotic EPOR signaling with increased phospho-NF-κB p65, along with obstruction induced ureteral dysfunction. EPO treatment improved ureteral peristalsis and suppressed ureteral apoptosis, via suppression of NF-κB activation and decreased expression of BAX that compensated for the decreased expression of BCL-2 and BCL-XL by obstruction.

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Attribution-NonCommercial-NoDerivatives 4.0 International